One major component of this project involves efforts to understand the functions of toll-like receptors (TLRs)in neuronal plasticity and neurodegenerative disorders. We discovered that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death in stroke. In another study we found that adult TLR3-deficient mice exhibited enhanced hippocampus-dependent working memory in the Morris water maze, novel object recognition, and contextual fear-conditioning tasks. In contrast, TLR3-deficient mice demonstrated impaired amygdala-related behavior and anxiety in the cued fear-conditioning, open field, and elevated plus maze tasks. Further, TLR3-deficient mice exhibited increased hippocampal CA1 and dentate gyrus volumes, increased hippocampal neurogenesis, and elevated levels of the AMPA receptor subunit GluR1 in the CA1 region of the hippocampus. In addition, levels of activated forms of the kinase ERK and the transcription factor CREB were elevated in the hippocampus of TLR3-deficient mice, suggesting that constitutive TLR3 signaling negatively regulates pathways known to play important roles in hippocampal plasticity. Direct activation of TLR3 by intracerebroventricular infusion of a TLR3 ligand impaired working memory, but not reference memory. Our findings reveal previously undescribed roles for TLR3 as a suppressor of hippocampal cellular plasticity and memory retention. In studies of relevance to Alzheimer's disease (AD) we found that TLR4 expression increases in neurons when exposed to amyloid beta-peptide (Abeta1-42) or the lipid peroxidation product 4-hydroxynonenal (HNE). Neuronal apoptosis triggered by Abeta and HNE was mediated by jun N-terminal kinase (JNK); neurons from TLR4 mutant mice exhibited reduced JNK and caspase-3 activation and were protected against apoptosis induced by Abeta and HNE. Levels of TLR4 were decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched control subjects, possibly as the result of loss of neurons expressing TLR4. Our findings suggest that TLR4 signaling increases the vulnerability of neurons to Abeta and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD. Other novel findings suggest important roles for TLRs in development of the nervous system. TLR3 protein is present in brain cells in early embryonic stages of development, and in cultured neural stem/progenitor cells (NPC). NPC from TLR3-deficient embryos formed greater numbers of neurospheres compared with neurospheres from wild-type embryos. Numbers of proliferating cells, as assessed by phospho histone H3 and proliferating cell nuclear antigen labeling, were also increased in the developing cortex of TLR3-deficient mice compared with wild-type mice in vivo. Treatment of cultured embryonic cortical neurospheres with a TLR3 ligand (polyIC) significantly reduced proliferating (BrdU-labeled) cells and neurosphere formation in wild type but not TLR3(-/-)-derived NPCs. Our findings reveal a novel role for TLR3 in the negative regulation of NPC proliferation in the developing brain. More recently we have obtained evidence that TLR3 plays important roles in adult neurogenesis and synaptic plasticity. Brain ischemia induces an inflammatory response involving activated complement fragments. In a preclinical study we showed that i.v. Ig (IVIG) treatment, which scavenges complement fragments, protects brain cells against the deleterious effects of experimental ischemia and reperfusion (I/R) and prevents I/R-induced mortality in mice. Animals administered IVIG either 30 min before ischemia or after 3 h of reperfusion exhibited a 50-60% reduction of brain infarct size and a 2- to 3-fold improvement of the functional outcome. Even a single low dose of IVIG given after stroke was effective. IVIG was protective in the nonreperfusion model of murine stroke as well and did not exert any peripheral effects. Human IgG as well as intrinsic murine C3 levels were significantly higher in the infarcted brain region compared with the noninjured side, and their physical association was demonstrated by immuno-coprecipitation. C5-deficient mice were significantly protected from I/R injury compared with their wild-type littermates. Exposure of cultured neurons to oxygen/glucose deprivationresulted in increased levels of C3 associated with activation of caspase 3, a marker of apoptosis; both signals were attenuated with IVIG treatment. Our data suggest a major role for complement-mediated cell death in ischemic brain injury and the prospect of using IVIG in relatively low doses as an interventional therapy for stroke. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se. Although vaccines that reduce A plaques can ameliorate cognitive deficits in animal models, they have failed in clinical trials due to serious side-effects. Old humans and mice usually respond poorly to vaccines due to presumably age-related immunological impairments. We found that by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike the A peptide vaccine, DNA immunizations with the amino-terminal A(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-A antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced A plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting A(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD.